4-amino-quinolines

ABSTRACT

NOVEL 4-AMINO-QUINOLINES OF THE FORMULA   4-(X-OOC-Y-NH-),R,R1-QUINOLINE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, -CF3, LOWER ALKYL, LOWER ALKOXY, LOWER ALKYLSULFONYLOXY, LOWER ALKYLTHIO, NITRO, LOWER ALKYLAMINO, LOWER ACYLAMINO AND CYANO, R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, CHLORINE AND METHYL, Y IS SELECTED FROM THE GROUP CONSISTING OF 2,3 AND 3,4-DISUBSTITUTED THIOPHENES OF THE FORMULA   R2-THIEN-2,3-YLENE AND R2-THIEN-3,4-YLENE   AND 4,5-DISUBSTITUTED THIAZOLES OF THE FORMULA   2-Q-THIAZOL-4,5-YLENE   WHEREIN R2 AND Q ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL AD X IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, A PHENYL, DILOWERALKYLAMINO LOWER ALKYLENE, N-MORPHOLINO LOWER ALKYLENE,   -CH2-CH(-O-R3)-CH2-O-R4, 2-P2-1,3-DIOXAN-5-YL, AND   -(CH2)N-N(+)(-M&#39;&#39;)2-M Z(-),   R3 AND R4 BEING HYDROGEN AND TAKEN TOGETHER FORM   -C(-P)(-P1)-   P AND P1 ARE LOWER ALKYL, P2 IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL AND MONOCYCLIC ARYL, M AND M&#39;&#39; ARE LOWER ALKYL, Z IS HALOGEN AND N IS AN INTEGER FROM 1 TO 6, AND THEIR NON-TOXIC, PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS HAVING ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY AND THEIR PREPARATION. LOWER ALKYL MEANS HAVING 1 TO 6 CARBON ATOMS.

United States Patent 3,808,216 4-AMINO-QU1NOLINES Andre Allais, LesLilas, Jean Meier, Coeuilly-Champrgny,

and Jean Cerede, Dugny, France, assignors to- Roussel- 5 UCLAF, Paris,France No Drawing. Filed Apr. 5, 1972, Ser. No. 241,405

Claims priority, appligzlatigzlsgrance, Apr. 8, 1971,

Int. Cl. C07d 33/60 U.S. Cl. 260-283 S 18 Claims ABSTRACT OF THEDISCLOSURE Novel 4-amino-quinolines of the formula NH-Y-COOX wherein Ris selected from the group consisting of hydrogen, halogen, CF loweralkyl, lower alkoxy, lower alkylsulfonyloxy, lower alkylthio, nitro,lower alkylamino, lower acylamino and cyano, R is selected from thegroup consisting of hydrogen, chlorine and methyl, Y is selected fromthe group consisting of 2,3 and 3,4-disubstituted thiophenes of theformula il m and 4,5-disubstituted thiazoles of the formula wherein Rand Q are selected from the group consisting of hydrogen and lower alkyland X is selected from the group consisting of hydrogen, lower alkyl, aphenyl, diloweralkylamino lower alkylene, N-morpholino lower P and P arelower alkyl, P is selected from the group consisting of lower alkyl andmonocyclic aryl, M and M are lower alkyl, Z is halogen and n is aninteger from 1 to 6, and their non-toxic, pharmaceuticallyacceptableacid addition salts having analgesic and anti-inflammatoryactivity and their preparation. Lower alkyl means having 1 to 6 carbonatoms.

OBJECTS OF THE INVENTION It is an object of the invention to provide thenovel quinolines of Formula I and their non-toxic, pharmaceuticallyacceptable acid addition salts.

It is a further object of the invention to provide a novel process forthe preparation of the compounds of Formula I.

It is another object of the invention to provide novel analgesic andanti-inflammatory compositions.

It is an additional object of the invention to provide a novel method oftreating pain and/or inflammation in warm blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The novel products of the invention are selected from thegroup consisting of 4-amin0-quinolines of the formula wherein R isselected from the group consisting of hydrogen, halogen, CF lower alkyl,lower alkoxy, lower alkylsulfonyloxy, lower alkylthio, nitro, loweralkylamino, lower acylamino and cyano, R is selected from the groupconsisting of hydrogen, chlorine and methyl, Y is selected from thegroup consisting of 2,3 and 3,4-disubstituted thiophenes of the formulaand 4,5-disubstituted thiazoles of the formula N-- as;

wherein R and Q are selected from the group consisting of hydrogen andlower alkyl and X is selected from the group consisting of hydrogen,lower alkyl, a phenyl, di-

loweralkylarnino lower alkylene, N-morpholino lower alkylene,

OHP2.

.GBM and(CHz)nNM' z R and R being hydrogen and taken together form P andP are lower alkyl, P is selected from the group consisting of loweralkyl and monocyclic aryl, M and M are lower alkyl, Z is halogen, and nis an integer from 1 to 6, and their non-toxic, pharmaceuticallyacceptable acid addition salts.

Examples of suitable acids for the formation of nontoxic,pharmaceutically acceptable acid addition salts are inorganic acids suchas hydrochloric acid and sulfuric acid and organic acids such as aceticacid, tartaric acid and citric acid. Suitable halogens for R and Z arefluorine, chlorine, bromine and iodine.

Examples of specific compounds of the invention are4-(2'-methoxycarbonyl-thienyl-3'-amino)-8-trifluoromethyl-quinoline andits hydrochloride,

4- (2'-carboXythienyl-3 '-amino -8-trifluoromethylquinoline,

the acetonide of 4-(2'-a-glyceryloxycarbonyl-thienyl-3'- amino)-8-trifiuoromethylquinoline,

4- 2'-a-glyceryloxycarbonyl-thienyl-3 -amino)-8-trifluoromethyl-quinoline and its hydrochloride,

4- (3 '-methoxycarbonyl-thienyl-4'-amino) -8-trifiuoro methyl-quinolineand its hydrochloride,

4- (3 '-carboxythienyl-4'-amino -8-trifluoromethylquinoline,

the acetonide of 4-(3'-a-glyceryloxycarbonyl-thienyl-4'- amino)-8-trifluoromethylquinoline,

4- (3 '-a-glyceryloxyc arbonyl-thienyl- 4'-amino -8-trifluoromethyl-quinoline and its hydrochloride,

4- (3-ethoxycarbonyl-5 -methyl-thienyl-2'-amino) -8-trifluoromethyl-quinoline and its hydrochloride,

4-(2-methoxycarbonylthienyl-3'-amino)-7-chloroquinoline and itshydrochloride,

4- (3 -carboxy-5 '-methyl-thienyl-2'-amino) -8-trifluoromethyl-quinoline,

4- 2'-carboxythienyl-3 '-amino) -7- chloro-quinoline,

the acetonide of 4-(3'-u-glyceryloxycarbonyl-5'-methylthienyl-2'-amino-8-trifluoromethyl-quinoline,

the acetonide of 4-(2'- z-glyceryloxycarbonyl-thienyl-3'- amino)-7-chloro-quinoline,

4- (3 '-a-glyceryloxycarbonyl-5 '-methy1-thienyl-2-amino)8-trifiuoromethyl-quinoline and its hydrochloride,

4-(2-a-glyceryloxycarbonyl-thienyl-3'-amino)7-chloroquinoline and itshydrochloride,

4-(2'-N-morpholinoethoxy-carbonyl-thienyl-3'-amino)-S-trifluoromethyl-quinoline and its dihydrochloride, and

4- (2-dimethylaminoethoxy-carbonyl-thienyl-3 '-amino)8-trifluoromethyl-quinoline and its dihydrochloride.

The novel process of the invention for the preparation of the quinolinesof Formula I comprises reacting in the presence of a strong acid a4-halo-quinoline of the formula Hal R1 wherein Hal is chlorine orbromine and R and R have the above meaning, with a compound of theformula wherein Y has the above definition to form a compound of FormulaI.

NH-Y-CO OX wherein X is lower alkyl in the form of a salt which istreated, if desired, with a base to obtain the corresponding free base.The said ester may be transformed by ester interchange into a compoundof Formula I:

wherein X is other than hydrogen or lower alkyl or, if desired, bysaponifying the said compound with a strong base to obtain a compound OfFormula I wherein X is hydrogen.

The acid addition salts of mineral or organic acids of the quinolines ofFormula I can be obtained by action with an appropriate acid and thequinolines.

Preferably, the condensation of halogenated quinoline of Formula H withthe compound of Formula HI is efiected with a dilute aqueous solution ofhydrochloric acid or sulfuric acid. Reaction of the salt of the loweralkyl ester is preferably effected with an organic base such astriethylamine, trimethylamine, pyridine or piperidine but inorganicbases such as alkali metal carbonates or bicarbonates may be used.

Saponification of the said lower alkyl esters of Formula I may beeffected by a strong base such as sodium hydroxide and potassiumhydroxide in an alcohol such as a lower alkanol like methanol, ethanolor isopropanol. The said lower alkyl esters of Formula I may besubjected to ester interchange with an alcohol other than a loweralkanol in the presence of an alkaline agent such as an alkali metalhydride, amide or alcoholate.

The free acid may be reacted in the presence of an acid catalyst with analcohol other than a lower alkanol and the acid may be in the form ofits acid halide or anhydride.

In one embodiment of the process, the lower alkyl ester of Formula I issubjected to an ester interchange with an alcohol of the formula MHO(CHz)nN and the resulting ester is reacted with an alkyl halide of theformula Z M to obtain the compound of Formula I wherein X is I)n M' Z1The said lower alkyl ester of Formula I may also be subjected to esterinterchange with an alcohol of the formula to obtain the ester ofFormula I wherein The ester interchange may first be effected withglycerine and the resulting 2,3-dihydroxypropyl ester is then reactedwith a ketone of the formula To form a compound of Formula I wherein Xis /CHr-O H CH CHzO the said lower alkyl ester may be subjected to esterinterchange with 2-P -5-hydroxy-1,3-dioxane or with 2-phenyl-5-hydroxy-1,3-dioxane followed by acid hydrolysis to obtain thecorresponding fl-glycerol ester which is then reacted with an aldehydeof the formula The 4-halo quinoline starting compounds are described inthe literature (Allais [Chim. Therapeutique, p. 65-70 (1966)], or may beprepared by analogous methods such as by the process described in FrenchPat. No. 1,514,- 280 starting from a suitable aniline.-

The analgesic and anti-inflammatory compositions of the invention arecomprised of an effective amount of a compound of Formula I or itsnon-toxic, pharmaceutically acceptable acid addition salts and apharmaceutical carrier. The compositions may be in the form ofinjectable solutions or suspensions in ampoules or auto-injectablesyringes or multiple dose flacons or in the form of tablets, coatedtablets, gelules, sublingual tablets, syrups, emulsions, granules oraromatic powders, suppositories, creams, ointments, gels, drops, powdersor collutoriums. The compositions may also contain other therapeuticprinciples such as spasmolytics, anticoagulants, antipyretics orsedatives.

The compositions due to their analgesic and anti-inflammatory activityare useful for the treatment of arthroses, lumbago, sciatic, shoulderpains and of myalgias. They ease pain, increase the mobility of joints,enlarge the perimeter of the gait and fight against anchylosis andinflammation.

The novel method of the invention for the treatment of pain and/orinflammation in Warm-blooded animals comprises administering towarm-blooded animals an effective amount of a compound of Formula I or anon-toxic, pharmaceutically acceptable acid addition salt thereof. Thesaid compounds may be administered transcutaneous- 1y, orally, rectally,perlingually, topically or transmucously. The usual daily dose is 0.15to 2 mg./kg. depending on the condition being treated and the specificcompound.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I 4- (2-methoxycarbonylthienyl-3 '-amino-8-trifluoromethylquinoline A mixture of 11.575 g. of4-chloro-8-trifluoromethylquinoline (obtained by process of Belgium Pat.No. 725,- 641), 7.85 g. of 2-methoxycarbonyl-3-amino-thiophene and 55ml. of 2 N hydrochloric acid was refluxed with stirring for three hoursand then the mixture was iced for 1 hour and vacuum filtered. Therecovered precipitate was empasted with ice water, vacuum filtered anddried under reduced pressure at 80 C. to obtain 16.45 g. of raw 4 (2methoxycarbonylthienyl 3 amino)-8-trifiuoromethyl-quinolinehydrochloride. The said raw product was dissolved in 20 ml. of methanolwith heating and the solution was filtered and the filter was Washedwith hot methanol. 7 ml. of triethylamine were added to the combinedfiltrates and after icing for 1 hour, the mixture was vacuum filtered.The precipitate was washed with iced methanol and dried under vacuum.The residue was dissolved in 850 ml. of refluxing methanol and thesolution was filtered hot. The filter was washed with boiling methanoland the filtrate was cooled and then iced for 1 hour and vacuumfiltered. The precipitate was empasted with iced methanol and dried invacuo to obtain 9.73 gm. of 4 (2' methoxycarbonylthienyl3'-amino)-8-trifiuoromethyl-quinoline melting at 177 C. The productoccurred as colorless needles soluble in chloroform, slightly soluble inmethanol and ethanol and insoluble in water.

Analysis: C H F N O S; molecular weight=352.33. Calculated (percent): C,54.54; H, 3.15; F, 16.18; N, 7.95; S, 9.10. Found (percent): C, 54.2; H,3.3; F, 16.0; N, 7.6; S, 8.8.

I.R. Spectrum (chloroform): Presence of associated NH at 3298 cmr ofcarbonyl at 1675 cmr of bands at 1621 and 1570 cm.- and of -CF Using thesame procedure, 4-chloro-8-trifiuoromethylquinoline and2-amino-3-ethoxycarbonyl-5-methyl-thiophene were reacted to form4-(3'-ethoxycarbonyl-5-methyl-thienyl-2-amino)-8-trifluoromethylquinoline melting at 158 C. and 4,7-dichloro-quinoline andZ-methoxycarbonyl-3-amino-thiophene were reacted to form 4-(2'-methoxycarbonyl thienyl 3-amino)-7-chloro-quinoline melting at 159 C.

EXAMPLE II 4- (2'-carboxythienyl-3'-amino) -8-trifluoromethylquinoline Amixture of 1.665 gm. of4-(2'-methoxycarbonyl-thienyl-3'-amino)-8-trifluoromethyl-quinoline, 150ml. of methanol and 10 ml. of N sodium hydroxide was refluxed forminutes and the mixture was then evaporated in vacuo to dryness. Theresidue was dissolved in 50 ml. of water and the pH was adjusted 5 to 6by addition of acetic acid. The mixture was iced for 1 hour and thenvacuum filtered. The precipitate was washed with water and dried in vacoat C. The residue was dissolved in 65 ml. of refluxing methanol and thesolution was filtered hot. The filter was washed with 20 ml. of boilingmethanol and 58 ml. of the solvent Was distilled off at normal pressure.The mixture was iced for 1 hour and vacuum filtered. The precipitate waswashed with iced methanol and dried in vacuo at 100 C. to obtain 1.21gm. of 4-(2'-carboxy thienyl-3-amino)-8-trifluoromethyl-quinolinemelting at 210-215 C. The product occured in the form of yellow needlessoluble in methanol and ethanol, slightly soluble in chloroform andinsoluble in water.

Analysis: C H F N O S; molecular weight=338.30. Calculated (percent): C,53.25; H, 2.68; F, 16.85; N, 8.28; S, 9.48. Found (percent): C, 53.2; H,2.9; F, 17.1; N, 8.0; ,S. 9.6.

I.R. Spectrum (Nujol): Presence of C=O at 1658 cm.-

Using the same method,4-(3-ethoxycarbonyl-5'-methylthienyl-2'-amino)-8-trifiuoromethyl-quinolinewas saponified to obtain4-(3-carboxy-5'-methyl-thienyl2'-amino)-S-trifiuoromethyl-quinolinemelting at 245 C. and 4- (2' methoxycarbonylthienyl-3'-amino)-7-chloro-quinoline was saponified to obtain4-(2'-carboxy-thienyl-3'-amino)-7-chloro-quinoline melting at 260 C.

EXAMPLE III Acetonide of 4-(2'-ot-glyceryloxycarbonyl-thienyl-3'- amino)-8-trifiuoromethyl-quinoline 100 ml. of2,2-dimethyl-4-hydroxymethyl-l,3-dioxolane, mg. of a 50% oily suspensionof sodium hydride and 12.27 gm. of4-(2-methoxycarbonyl-thienyl-3'-amino)-8- trifiuoromethylquinoline weremixed with agitation and the mixture was then heated under reducedpressure of 30 to 50 mm. Hg for 3 hours at 90 C.i5 C. The mixture wascooled to 20 C. and after 250 ml. of water were added, the mixture wasagitated for 20 minutes. The mixture was vacuum filtered and theprecipitate was washed with ice water and dried in vacuo. The residuewas dissolved in 60 ml. of hot methylene chloride and the solution wasfiltered. The filter was washed with methylene cipitate was washed withiced isopropyl ether and dried to the filtrate, 360 ml. of the solventwere distilled oif. The residue was iced for 1 hour and vacuum filtered.The preciptate was washed with iced isopropyl ether and dried in vacuoto obtained 13.65 gm. of the acetonide of4-(2'uglyceryloxy-carbonyl-thienyl-3-amino)-8 trifluoromethyl-quinolinemelting at 138 C. The product occurred in the form of colorless needlessoluble in chloroform and alcohols and insoluble in water.

Analysis: C H F N O S; molecular weight=452.'44. Calculated (percent):C, 55.74; H, 4.23; F, 12.60; N, 6.19; S, 7.09. Found (percent): C, 56.0;H, 4.4; F, 12.6; N, 6.0; S, 7.3.

Using the same procedure, 4(3' ethoxycarbonyl-'- methyl-thienyl-2-amino)8 trifluoromethyl-q-uinoline was reacted to form the acetonide of4-(3'-u-glyceryloxycarbonyl-5'-methyl-thienyl 2'amino)-8-trifluoromethyl-quinoline melting at 139 C. and4-(2-methoxycarbonyl-thienyl-3-amino) 7 chloro-quinoline was reacted toform the acetonide of4-(2'-a-glyceryloxycarbonyl-thienyl-3-amino)-7-chloro-quinoline meltingat 110 C., 4-(2- methoxycarbonyl-thienyl-3'-amino) 8trifluoromethylquinoline was reacted with fl-N-morpholinoethanol and theproduct was then acidified with hydrochloric acid to form thedihydrochloride of 4-(2'-N-morpholinoethoxycarbonyl thienyl 3amino)-8-trifluoromethyl-quinoline (M.P. =208 C.), or withB-dimethylaminoethanol and the product was acidified with hydrochloricacid to form the dihydrochloride of4-(2-dimethylaminoethoxycarbonyl-thienyl-3'-amino) 8trifluoromethyl-quinoline melting at 198 C.

EXAMPLE IV 4- (2'-a-glyceryloxycarbonyl-thienyl-3 -amino-8-trifluoromethylquinoline A mixture of 10.5 gm. of the acetonide of4-(2'-a-glyceryloxycarbonyl-thienyl-3-amino) 8 trifluoromethylquinolineand 50 ml. of water was heated with agitation at 95 C.100 C. and theniced for 1 hour and vacuum acid were added, the mixture was agitated for15 minutes at 95 C.100 C. and then iced for 1 hour and vacuum filtered.The product was dried in vacuo to form 10.04 gm. of 4(2'-a-glyceryloxycarbonyl-thienyl-3'-amino)-8- tritiuoromethyl-quinolinehydrochloride melting at about 150 C. The 10.04 gm. of hydrochloridewere dissolved in 30 ml. of warm methanol and after the solution wasfiltered, 5 ml. of triethylamine were added to the filtrate. The mixturewas iced for 1 hour and vacuum filtered. The precipitate was washed withiced methanol and dried in vacuo. The residue was dissolved in 55 ml. ofrefluxing methanol and the solution was filtered hot. The filter waswashed with boiling methanol and the filtrate was iced for 1 hour andvacuum filtered. The precipitate was washed with iced methanol and driedto obtain 7.15 gm. of 4- (2'-a-glyceryloxycarbonyl-thienyl-3'-amino) 8trifluoromethyl-quinoline melting at 163 C. The product occurred in theform of colorless needles soluble in ethanol, slightly soluble inchloroform and insoluble in water.

Analysis: C H F N O S; molecular weight=410.38. Calculated (percent): C,52.42; H, 3.67; F, 13.82; N, 6.79; S, 7.77. Found (percent): C, 52.5; H,3.3; F, 14.2; N, 6.6; S, 7.6.

I.R. Spectrum (Nujol): Band at 1583 cm.

Using the same procedure, the hydrochloride of 4-(2-a-glyceryloxycarbonyl-thienyl 3' amino)-8-trifluoromethyl-quinoline wasprepared by the action of hydrochloric acid on 4-(2-u-glyceryloxycarbonyl thienyl-3-amino)- 8-trifluoromethyl-quinolinein a methanol solution. The said product became sticky at 170 C. and hadan instantaneous M.P. at about 200 C. and the acetonide of 4-(3'-u-glyceryloxycarbonyl-5-methyl-thienyl 2' amino)-8-trifluoromethyl-quinoline was reacted to form4-(3-uglyceryloxycarbonyl-S-methyl-thienyl-2'-amino) 8trifluoromethyl-quinoline melting at 205 C. Also, the acetonide of4-(2-a-glyceryloxycarbonyl-thienyl-3'-amino)- 7-chloro-quinoline wasreacted to form4-(2-a-glyceryloxycarbonyl-thienyl-3'-amino)-7-chloro-quinoline meltingat 166 C.

EXAMPLE V 4- (3 '-methoxycarbonyl-thienyl-4-amino-8-trifluoromethyl-quinoline A mixture of 18.52 gm. of4-chloro-8-triflluoromethylquinoline, 17.2 gm. of3-methoxycarbonyl-4-amino-thiophene hydrochloride and 90 ml. of Nhydrochloric acid was refluxed with agitation under an inert atmospherefor 45 minutes and, then was filtered. The filter was washed with hot Nhydrochloric acid and the combined filtrates were ice-cooled for 1 hourand vacuum filtered. The precipitate was empasted with a little icewater and then was dissolved in .50 ml. of hot methanol. 50 ml. of waterwere added followed by 8.5 ml. of triethylamine. The mixture wasice-cooled for 1 hour and vacuum filtered. The precipitate was washedwith an iced methanol-water (1:1) mixture and dried in vacuo. Theresidue was dissolved in 1,250 ml. of refluxing methanol and thesolution was treated with active charcoal and filtered hot. The filterwas washed with boiling methanol and the filtrate was concentrated toabout 300 ml. and then chilled for 1 hour and vacuum filtered. Theprecipitate was washed with iced methanol and dried in vacuo. Theresidue was recrystallized under the same conditions to obtain a 39%yield of 4-(3-methoxycarbonyl-thienyl-4'-amino)-8-trifluoromethylquinoline melting at 193l94 C. The product occurred ascolorless needles soluble in chloroform, slightly soluble in alcoholsand insoluble in water.

Analysis: C H F N O S: molecular Weight=352.33. Calculated (percent): C,54.54; H, 3.15; N, 7.95; F, 16.18; S, 9.10. Found (percent): C, 54.2; H,3.1; N, 7.8; F, 16.1; S, 9.4.

LR. Spectrum (chloroform): Presence of C=O at 1696 cm.- and of NH at3333 cm.-

EXAMPLE VI 4- (3 '-carboxy-thienyl-4'-amino -8-trifluoromethylquinolineA mixture of 3.81 gm. of4-(3-methoxycarbonyl-thienyl-4'-amino)-8-trifluoromethyl-quinoline, 50ml. of methanol and 30 ml. of 2 N sodium hydroxide was refluxed for 1%hours under an inert atmosphere and the methanol expelled under partialvacuum. 70 ml. of water were added and the mixture was heated to C., andthen filtered. The filter was washed with boiling water and the combinedfiltrates 6 ml. of acetic acid at 80 C. were added. The mixture wasice-cooled for 1 hour and vacuum filtered. The precipitate was washedwith water and dried in vacuo at 80 C. The residue was dissolved in 150ml. of refluxing methanol and the solution was filtered hot. The filterwas washed with 25 ml. of boiling methanol and 120 ml. of the solventdistilled off. The mixture was icecooled for 1 hour and vacuum filtered.The precipitate was washed with iced methanol and dried in vacuo at 80C. to obtain 3.4 gm. of 4-(3'-carboxy-thienyl-4'-amino)-8-trifluoromethyl-quinoline melting at 200 C. The product occurred inthe form of yellow needles soluble in alkaline aqueous solutions,slightly soluble in methanol and acetone and insoluble in water andchloroform.

Analysis: C H F N O S; molecular Weight=338.30. Calculated (percent): C,53.25; H, 2.68, N, 8.28, F. 16.85; S, 9.48. Found (percent): C, 53.6; H,3.0. N, 8.1; F, 16.5; S, 9.4.

I.R. Spectrum (Nujol): Presence of acid. Absorption reg-ion ofassociated NHOH.

EXAMPLE VII Acetonide of 4-(3-u-glyceryloxycarbonyl-thienyl-4'- amino-8-trifluoromethyl-quinoline ml. of2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 200 mg. of sodium hydridein a 60% suspension in Vaseline oil was mixed, 11.4 gm. of4-(3'-methoxycarbonyl-thienyl-4'-amino)-8-trifluoromethyl-quinoline wereadded thereto. The mixture was agitated at a vacuum of 30 mm. Hg andheated for 5 hours at 83 C. and then cooled to 25 C. under vacuum. 200ml. of water were added at normal pressure and with agitation, and themixture was agitated for 20 minutes and vacuum filtered. The precipitatewas washed with water and dried in vacuo at 80 C. The residue wasdissolved in 250 ml. of isopropyl ether and 50 ml. of methylene chlorideat reflux and the solution was treated with active charcoal and filteredhot. The filter was washed with 150 ml. of a hot isoprop lether-methylene chloride mixture (5 :1) and then 260 mL of the solventsdistilled off from the filtrate. The mixtme was ice-cooled for 1 hourand vacuum filtered. The precipitate was washed with iced isopropylether and dried in vacuo at 80 C. to obtain 11.53 gm. of the acetonideof 4- 3-a-glyceryloxycarbonyl-thienyl-4-amino)-8-trifluoromethyl-quinoline melting at 137 C. The product occurred as acolorless solid soluble in chloroform, alcohols and acetone andinsoluble in water.

Analysis: C H F N O S; molecular weight=452.44. Calculated (percent): C,55.75; 'H, 4.23; N, 6.19; F, 12.60; S, 7.09. Found (percent): C, 55.7;H, 4.5; N, 5.7; F, 12.6; S, 7.2.

I.R. Spectrum (chloroform): Presence of :0 at 1704 cm.- of cyclic COC at3333 cmr of arcmatic and conjugated C=C at 1595, 1585, 1569, 1538 and1508 cm.- and of CF EXAMPLE VIII 4-(3'-u-glyceryloxycarbonyl-thienyl-4'amino)-8- trifluoromethyl-quinoline 8 gm. of the acetonide of4-(3-u-glyceryloxycarbonylthienyl-4'-amino)-8-trifluoromethyl-quinolinewere suspended in 48 ml. of water and the mixture heated to 95 C. 4 ml.of concentrated hydrochloric acid were added thereto and the mixture wasagitated for 10 minutes at 95 C. The solution was brought back to roomtemperature, and after a solution of 10 gm. of sodium acetate in 20 ml.of water was added, the mixture was ice-cooled for 1 hour and vacuumfiltered. The precipitate was empasted with water and dried in vacuo at80 C. The residue was dissolved in 350 ml. of refluxing acetone and thesolution was filtered. The filter was washed with 100 ml. of hot acetoneand 370 ml. of the solvent Was distilled 01f. The mixture was ice-cooledfor 1 hour and vacuum filtered. The precipitate was washed with icedacetone and dried in vacuo at 80 C. to obtain 5.34 gm. of4-(3'-aglyceryloxycarbonylthienyl 4'-amino)-8-trifluoromethylquinolinemelting at 192 C.-193 C. The product occurred in form of yellow needlessoluble in ethanol, slightly soluble in methanol and acetone andinsoluble in water and chloroform.

Analysis: C I-I F N O S- molecular weight=412.38. Calculated (percent):C, 52.42; H, 3.67; N, 6.80; F, 13.82; S, 7.77. Found (percent): C, 52.6;H, 3.7; N, 6.4; F, 13.4; S, 8.1.

I.R. Spectrum (Nujol): Presence of C=O at 1696 cm.- and of C=C andaromatic at 1623, 1597, 1547 and 1512 cm.-

PHARMACOLOGICAL STUDY (A) Analgesic activity The test used was based onthe fact noted by R. Koster et a1. (Fed. Proc., 1959, vol. 18, page 412)wherein the intraperitoneal injection of acetic acid causes in micecharacteristic repeated stretching and twisting movements which canpersist for more than six hours. Analgesics prevent or suppress thissyndrome which, therefore, can be considered as externalization of adiffuse abdominal pain.

A solution of 6% acetic acid in water containing 10% arabic gum was usedand the dose which released the syndrome under these conditions was 0.01cc./gm., that is 60 mg./kg. of acetic acid. The test compounds wereadministered orally one-half hour before the intraperitoneal injectionof acetic acid, the mice having fasted since the night before theexperiment. For each dose and for each control, which are obligatory foreach test, a group of animals was used. For each mouse, the stretchingswere observed and counted and then added for the group of 5 during aperiod of 15 minutes starting immediately after the injection of aceticacid.

Table I summarizes the results.

Table I shows that the 3 compounds possess a considerable analgesicactivity and that their 50% active doses (DA are 500 to 1 mg./kg., 2mg./kg. and 5 mg./ kg. respectively.

(B) Anti-inflammatory activity The test was the slightly modified testof Branceni et al. [Arch. Int. Pharmacodyn. (1954), vol. 152, p. 15]. Itconsists of administering to rats weighing about gm., a single injectionof 1 mg. of naphthoylheparamine (N-HJA.) under the plantar aponevrosisof a hind paw. This injection is intended to provoke the formation of aninflammatory edema. The test products are administrated orally in anaqueous suspension one hour before the irritating injection. Theinflammation is measured by plethysmography with an electricalplethysmomete'r and the paw is measured immediately before and two-hoursafter the irritating injection. The increase in the volume of the pawbetween the two measurements represents the degree of inflammation. Theaverage degree of inflammation for each group is expressed in absolutevalues and in percentage of those of the control animals. Under theseconditions, the most adequate active standard dosage for calculating theactivity of a product is the DA or the dosage which diminishes thedegree of inflammation by 40% in comparison to that of the controls. Theproducts tested were in an aqueous suspension and were administered atincreasing doses. The obtained results are in Table II.

TABLE II Degree 0! Admin- Increase of inflammation istered the volume inpercent doses in of the paw of that of mgJkg. after 2 hrs. the controls4-(2-carboxythienyl-3-amino)- S-trifluoromethylqulnohne Control 29. 4 5014. 3 52 Control 21.3 20 19. 4 264-(2-a-glyceryloxycarbonylthienyl-3-amino)-8-trifiuoromethylquinolineControl 27. 5

10 18. 0 35 Control 31. 4 20 19. 9 37 Control 29. 4 50 16. 1 45Acetonlde o1 4-(2'-a-glyceryloxycarbony1th1enyl-3-amino)-8-trifluoromethylquinoline Control 27. 5 10 22. 0 20 Control 31. 4 5O 17.9 43 Table II shows that the 3 products possess a clear antiinflammatoryactivity and that their DA are 33 mg./kg.,

25 mg./ kg. and 40 mg./ kg. respectively. H Various modification of thecompositions and methods of the invention may be made without departingfrom the spirit or scope thereof and it is to be understood that theclaims are to be limited only as defined in the appended claims.

We claim:

1. A compound selected from the group consisting of 4-amino-quinolinesof the formula wherein R is selected from the group consisting ofhydrogen, halogen, CF lower alkyl, lower alkoxy, lower alkylsulfonyloxy,lower alkylthio, nitro, lower alkylamino, lower alkanoylamino, andcyano, R is selected from the group consisting of hydrogen, chlorine andmethyl, Y is selected from the group consisting of 2,3- and 3,4-disubstituted thiophenes of the formula and 4,5 disubstituted thiazolesof the formula wherein R and Q are selected from the group consisting ofhydrogen and lower alkyl and X is selected from the group consisting ofhydrogen, lower alkyl, phenyl, diloware lower alkyl, Z is halogen and nis an integer from 1 to 6 and their non-toxic, pharmaceuticallyacceptable acid salts.

2. The compound of claim 1 which is selected from the group consistingof 4-(2-methoxycarbonyl-thienyl- 3-amino)-8-trifluoromethyl-quinolineand its hydrochlo- 6 ride.

3. The compound of claim 1 which is selected from the group consistingof 4-(2'-a-glyceryloxycarbonyl-thienyl-3'-amino) 8trifluoromethyl-quinoline and its bydrochloride.

4. The compound of claim 1 which is selected from the group consistingof 4-(3'-methoxycarbonyl-thienyl-4'- amino)-8-trifiuoromethyl-quinolineand its hydrochloride.

5. The compound of claim 1 which is selected from the group consistingof 4-(3 a glyceryloxycarbonylthienyl-4-amino) 8trifluoromethyl-quinoline and its hydrochloride.

6. The compound of claim 1 which is selected from the group consistingof 4-(3 ethoxycarbonyl-5-methyl thienyl-2'-amino) 8trifiuoromethyl-quinoline and its hydrochloride.

7. The compound of claim 1 which is selected from the group consistingof 4-(2-methoxycarbonyl-thienyl- 3-amino)-7-chloro-quinoline and itshydrochloride.

8. The compound of claim 1 which is selected from the group consistingof 4-(3'-u-glyceryloxycarbonyl-thienyl-2'-amino) 8trifluoromethyl-quinoline and its hydrochloride.

9. The compound of claim 1 which is selected from the group consistingof 4-(2--glyceryloxycarbonyl-thienyl- -amino)-7-chloro-quinoline and itshydrochloride.

10. The compound of claim 1 which is selected from the group consistingof4-(2'-dimethylaminoethoxycarbonylthienyl-3-a.mino)8-trifiuoromethyl-quinolineand its dihydrochloride.

11. The compound of claim 1 which is 4-(2'-carboxythienyl-3 '-aminoS-trifluoromethyl-quinoline.

12. The compound of claim 1 which is 4-(3'-carboxythienyl-4'-amino -8-trifiuoromethyl-quino1ine.

13. The compound of claim 1 which is the acetonide of4-(3'-a-glyceryloxycarbonyl-thienyl 4' amino)-8-trifiuoromethyl-quinoline.

14. The compound of claim 1 which is 4-(3'-carboxy-5'-methyl-thienyl-2'-amino)-8-trifluoromethyl-quinoline.

15. The compound of claim 1 which is 4-(2-carboxythienyl--amino)-7-chloro-quinoline.

16. The compound of claim 1 which is the acetonide of4-(3-a-glyceryloxycarbonyl 5 methyl-thienyl-2'- amino)-8-trifiuoromethyl-quinoline.

17. The compound of claim 1 which is the acetonide of4-(2'-a-glyceryloXycarbonyl-thienyl 3' amino)-7- chloro-quinoline.

18. The compound of claim 1 which is the acetonide of4-(2'-a-glyceryloxycarbonyl-thienyl 3' amino)-8-trifiuoromethyl-quinoline.

References Cited UNITED STATES PATENTS 3,150,047 I 9/1964 Allais et a1.260287 R 3,151,026 9/ 1964 Allais et al 260-287 X 3,174,972 3/ 1965Allais et al 260287 X 3,232,944 1/ 1966 Allais et al 260-287 R 3,458,5191/ 1969 Scherren 260--287 R 3,389,171 6/1968 Montzka 260--283 S3,502,681 3/ 1970 Allais et al. 260--287 OTHER REFERENCES Taurins etal.: Chem. Abstr., vol. 74, col. 22 749f (1971).

Allais et al.: Chimie Therapeutic, 1966, pp. 65-70.

Burger: Medicinal Chemistry, 2d edition, Interscience, 1960, p. 42, 497.

DONALD G. DAUS, Primary Examiner US. 01. X.R.

260-247.2 B, 283.2, 283 CN, 286 Q, 286 R, 287 R, 333.2; 424248, 250.

I UNITED STATES PATENT OFFICE (ZERfEi'FlC-A'TE ()F CORRECIION Patent No.3 808 216 Dated April 30 1974 Andre Allais et a1.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

H H I-.. Column 5, line 69, C H P N O S should read line 63, "cipitatewas Washed with iced isopropyl ether and C H F N O S Column 6, line 22,"vaco" should read vacuo dried" should read chloride and after 400 ml ofisopropyl ether were added Column 7, line- 27, "at 95 C -l00C and theniced for 1 hour and vacuum" should read at 95C and after 5ml ofconcentrated hydrochloric Column ll, claim 1, line 43,

portion of the formula reading CH ..O CH-O z 2 CH 7 CHP should read -CHCHP 2 M PCP-05o H069) uscoMM-Dc 80376-P69 U 5 GOVERNMENT PRlNYINGOFFICE:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,808,216 Dated April 30, 1974 Inventor s Andre Allals et a1 P 2 I It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 11., claim 1, lines 45 to 49, the portion of the formula readingM/ G) 6 (cH N 2 should read Signed and sealed this 8th day of October1974.

(SEAL) Attest:

MCCOY M. GIBSON JR. c. MARSHALL DANN Attesting Officer Commissioner ofPatents FORM PC4050 (10-69) USCOMMJDC eosnbl eg u 5 GOVERNMENT mmmucorncz: 930

